Simian AIDS induced by SIVmac251/239 is characterized by an accelerated disease progression and by higher set-point plasma viral loads (VLs) compared to HIV-1 infection in humans. The highly pathogenic SIVmac251 originated from serial passages of cross-species transmitted SIVsm from sooty mangabeys SMs) to rhesus macaques (Rh). We propose a new paradigm of AIDS pathogenesis in Rh. Our data strongly indicate that primary SIVsm isolates are less pathogenic in Rh than serially passaged SIVmac251/239. We hypothesize that this low intrinsic pathogenic potential is due to the ability of the host to contain the infection rather than a lower replicative capacity of the virus. A corollary of this hypothesis is that these primary SIVsm isolates may represent an improved model for AIDS, useful for pathogenesis of HIV/SIV infection and vaccine development. To confirm our hypothesis, we propose the following specific aims (SA): Specific Aim 1: To assess the in vivo pathogenesis of primary SIVsm strains belonging to selected SIVsm lineages and to compare them to the highly pathogenic prototype SIVmac251. We will extend the preliminary results to acquire statistically significant data and confirm that SIVsm can indeed be controlled by Rh. This aim consists of 4 parts: SA1 A. To study the in vivo dynamics of primary SIVsm isolates replication in Rh; SA1B. To investigate if the low viral load (VL) set-points in Rh infected with primary SIVsm isolates are due to a more restrictive in vivo tropism; SA1C. To investigate the adaptive immune responses in Rh infected with primary SIVsm isolates; SA1D. To investigate the dynamics of major target cell populations in peripheral blood, lymphoid and intestinal tissues in order to determine if primary SIVsm isolates induce less CD4 destruction. Specific Aim 2: To dissect the adaptive immune responses (cellular versus humoral) potentially responsible for increased control of VL in infection with primary SIVsm isolates. The experimental approach includes (a) depletion of CD8+ cells during the acute and chronic phase of infection and (b] depletion of CD20+ cells during the acute phase of infection with a neutralizable SIVsm strain. This new macaque model is highly relevant for public health. Characterizing a group of viruses which are better controlled by the immune system will offer the opportunity to carry out studies to identify the correlates of immune protection in HIV/SIV infections. By providing an array of SIVsm strains showing roughly the same degree of divergence as HIV-1 group M subtypes, our model may be used for the study of heterotypic protection.